Cephem derivatives

ABSTRACT

Compounds, represented by the following formula (I), having a β-(substituted or unsubstituted imidazo 5,1-b!thiazolyl)vinyl group at the 3-position of the cephem ring and a salt and an ester thereof are disclosed. The compounds have antibacterial activity against a very wide spectrum of bacteria and potent antibacterial activity against Gram-positive bacteria, Gram-negative bacteria, and resistant bacteria. ##STR1## wherein X represents CH or N, R 1  represents a hydrogen atom or an amino protective group, R 2  represents a hydrogen atom, a C 1-6  alkyl group, a C 3-7  cycloalkyl group, or a hydroxy protective group, R 3  is absent or represents a hydrogen atom, a salt forming cation, or a carboxyl protective group, R 4 , R 5 , and R 6 , which may be the same or different, each independently represent a hydrogen atom or a C 1-6  alkyl group, R 7+   is absent or a cation of a C 1-6  alkyl, and n is an integer of 0 to 1.

This is a 371 of PCT/JP96/01406 filed May 24, 1996.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to novel β-lactam antibiotics andpharmaceutically acceptable salts and esters thereof. More particularly,the present invention relates to novel cephem compounds havingantibacterial activity and pharmaceutically acceptable salts and estersthereof.

2. Background Art

Cephem antibiotics exhibit excellent antibacterial activity with lowtoxicity for mammals. They are therefore very important to the treatmentof infectious diseases in mammals. In recent years, cephem derivativeshaving an aminothiazolylacetyl group at the 7-position of the cephemring have been found to have potent antibacterial activity and stabilityagainst β-lactamase, leading to numerous studies and developments inthese cephem derivatives. Various semi-synthetic cephem compounds havealready been put on the market and clinically used as therapeutic agentsfor various infectious diseases.

However, among these compounds, those usable as a therapeutic agenthaving antibacterial activity against Pseudomonas aeruginosa andMyxomycetes are limited. Further, these compounds are unstable againstβ-lactamase produced by resistant bacteria and have drawbacks such aslow antibacterial activity against the resistant bacteria which haveposed a clinical problem these days. Furthermore, many cephemantibiotics have been developed for use in injections, and it is oftenpointed out that, in the case of oral administration, the cephemantibiotics have low absorption ratio and, hence, have unsatisfactoryefficacy.

Specific examples of β-lactam compounds known in the art includeCefixime, Cefdinir, ME 1207 (Cefditren pivoxil), and ME 1206(Cefditren).

However, no compounds having a β-substituted vinyl side chain,especially a β-(substituted or unsubstituted imidazo5,1-b!thiazolyl)vinyl group, at the 3-position of the cephem ring havebeen reported so far as the present inventors know.

SUMMARY OF THE INVENTION

The present inventors have now found that compounds having aβ-(substituted or unsubstituted imidazo 5,1-b!thiazolyl)vinyl group atthe 3-position of the cephem ring have antibacterial activity against avery wide spectrum of bacteria and potent antibacterial activity againstGram-positive bacteria, Gram-negative bacteria, and resistant bacteria.

Thus, an object of the present invention is to provide novel cephemderivatives having potent antibacterial activity against a wide spectrumof bacteria.

Another object of the present invention is to provide pharmaceuticalcompositions comprising the cephem derivative of the present invention.

A further object of the present invention is to provide a method fortreating infectious diseases, comprising the step of administering thecephem derivative of the present invention.

The compounds according to the present invention are cephem derivativesrepresented by the following formula (I): ##STR2## wherein X representsCH or N, R¹ represents hydrogen or an amino protective group,

R² represents hydrogen; C₁₋₆ alkyl in which one or more hydrogen atomsmay be substituted by halogen, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl,N-C₁₋₄ alkylcarbamoyl, cyano, amino, or C₁₋₄ alkylamino; C₂₋₄ alkenyl;C₂₋₄ alkynyl; C₃₋₇ cycloalkyl; or a hydroxy protective group,

R³ is absent or represents hydrogen, a salt forming cation, or acarboxyl protective group,

R⁴, R⁵, and R⁶, which may be the same or different, each represent

hydrogen;

C₁₋₄ alkoxy;

C₁₋₄ alkylthio;

cyano;

carboxyl;

C₁₋₄ alkoxycarbonyl;

carbamoyl;

N-C₁₋₄ alkylcarbamoyl;

formyl;

amino in which one or more hydrogen atoms may be substituted by formyl,C₁₋₄ alkylcarbonyl, or C₁₋₄ alkylsulfonyl;

halogen;

C₁₋₆ alkyl in which one or more hydrogen atoms may be substituted by agroup selected from the group consisting of hydroxyl, C₁₋₄ alkoxy,mercapto, C₁₋₄ alkylthio, cyano, halogen, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, N-C₁₋₄ alkylcarbamoyl, formyl, alkylcarbonyl, hydroxyimino,C₁₋₄ alkoxyimino, amino, formylamino, C₁₋₄ alkylcarbonylamino,halogen-substituted C₁₋₄ alkylcarbonylamino, carbamoyloxy, N-C₁₋₄alkylcarbamoyloxy, C₁₋₄ alkylsulfonylamino, ureido, N-C₁₋₄ alkylureido,C₁₋₄ alkylcarbonylamino, and imino-C₁₋₄ alkylamino;

C₃₋₆ cycloalkyl;

C₂₋₄ alkenyl; or

C₂₋₄ alkynyl or

any two of R⁴, R⁵, and R⁶ may together represents C₃₋₆ alkylene whereone or more methylene groups in this alkylene group may be replaced by--NH--, --O--, --S--, or --CO--,

R⁷⁺ is absent or represents a cation of C₁₋₆ alkyl, substituted C₁₋₆alkyl, or substituted C₁₋₆ alkylene, and

n is an integer of 0 to 1; and

pharmaceutically acceptable salt and ester thereof.

The compounds represented by the formula (I) have antibacterial activityagainst a very wide spectrum of bacteria and potent antibacterialactivity against Gram-positive bacteria, Gram-negative bacteria, andresistant bacteria. The antibacterial activity of these compounds issuperior to that of Cefixime, Cefdinir, and ME 1206 having chemicalstructures analogous to that of the compounds of the present invention.In particular, the compounds of the present invention have very potentantibacterial activity against Staphylococcus aureus (MSSA and MRSA) andEnterococcus (faecalis).

DETAILED DESCRIPTION OF THE INVENTION

Definitions

As used herein, the term "alkyl" as a group or a part of a group means astraight or branched chain. Specific examples thereof include methyl,ethyl, propyl, iso-propyl, n-butyl, iso-butyl, and t-butyl. The term"halogen" means a fluorine, chlorine, bromine, or iodine atom. The term"aryl" preferably means phenyl, naphthyl, and tolyl.

Compounds

In the formula (I), the protective group, for an amino group,represented by R¹ is preferably a group which can be easily removed byacid hydrolysis or the like. Specific examples thereof includealkoxycarbonyl groups, such as a t-butoxycarbonyl group, acyl groups,such as formyl and chloroacetyl groups, and a trityl group.

In the formula (I), the hydroxy protective group represented by R² maybe, for example, a trityl, t-butyldimethylsilyl, trimethylsilyl,triethylsilyl, allyloxycarbonyl, p-methoxybenzyloxycarbonyl, orp-nitrobenzyloxycarbonyl group. Preferred examples of R² include C₁₋₆alkyl (more preferably, C₁₋₄ alkyl) and halogen-substituted C₁₋₆ alkyl(more preferably, halogen-substituted C₁₋₄ alkyl) groups and hydroxyprotective groups (for example, trityl, methoxymethyl,methoxyethoxymethyl, formyl, and tetrahydropyranyl groups).

In the formula (I), when R³ is absent, the carboxyl group, to which R³is attached, may be free --COO⁻ or, when R⁷⁺ described below is present,may form an intramolecular salt. Preferred examples of the salt-formingcation represented by R³ include cations of an alkali metal salt, analkaline earth metal salt and an ammonium salt. The carboxyl protectivegroup represented by R³ may be a protective group generally used forcephalosporin. Preferred examples thereof include aryl, lower alkyl,lower alkoxymethyl, lower alkylthiomethyl, lower alkanoyloxymethyl,lower alkoxycarbonyloxyalkyl, lower alkylcarbonyloxyalkyl, andoptionally substituted (2-oxo-1,3-dioxolen-4-yl)methyl groups.Metabolically unstable protective groups which can be hydrolyzed in vivoand removed are particularly preferred. Specific examples of suchprotective groups include lower alkoxymethyl, lower alkylthiomethyl,lower alkanoyloxymethyl, lower alkoxycarbonyloxyalkyl, loweralkylcarbonyloxyalkyl, and optionally substituted(2-oxo-1,3-dioxolen-4-yl)methyl groups.

There is no particular limitation on the position of the imidazo5,1-b!thiazolyl group which is attached to a vinyl group present in the3-position of the cephem skeleton. However, the 2-, 3-, 5-, or7-position of the imidazo 5,1-b!thiazolyl group is preferred.

At least one hydrogen atom on the imidazo 5,1-b!thiazolyl group may besubstituted. The substituents are represented by R⁴, R⁵, and R⁶ in theformula (I). R⁴, R⁵, and R⁶ may be the same or different and eachrepresent hydrogen; C₁₋₄ alkoxy; C₁₋₄ alkylthio; cyano; carboxyl; C₁₋₄alkoxycarbonyl; carbamoyl; N-C₁₋₄ alkylcarbamoyl; formyl; amino in whichone or more hydrogen atoms may be substituted by formyl, C₁₋₄alkylcarbonyl, or C₁₋₄ alkylsulfonyl; halogen; C₁₋₆ alkyl in which oneor more hydrogen atoms may be substituted by group selected from thegroup consisting of hydroxyl, C₁₋₄ alkoxy, mercapto, C₁₋₄ alkylthio,cyano, halogen, carboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, N-C₁₋₄alkylcarbamoyl, formyl, alkylcarbonyl, hydroxyimino, C₁₋₄ alkoxyimino,amino, formylamino, C₁₋₄ alkylcarbonylamino, halogen-substituted C₁₋₄alkylcarbonylamino, carbamoyloxy, N-C₁₋₄ alkylcarbamoyloxy, C₁₋₄alkylsulfonylamino, ureido, N-C₁₋₄ alkylureido, C₁₋₄ alkylcarbonylaminoand imino-C₁₋₄ alkylamino); C₃₋₆ cycloalkyl; C₂₋₄ alkenyl; or C₂₋₄alkynyl. Any two of R⁴, R⁵, and R⁶ may together represent C₃₋₆ alkylene,where one or more methylene groups in this alkylene group may besubstituted by --NH--, --O--, --S--, or --CO--. When R⁴, R⁵, and R⁶represent halogen, the halogen atom is preferably a fluorine or chlorineatom. The position of these substituents R⁴, R⁵, and R⁶ is preferablythe 2-, 3-, 5-, and 7-positions of the imidazo 5,1-b!thiazolyl group.

According to a preferred embodiment of the present invention, a group ofcompounds having C₁₋₆ alkyl (more preferably, C₁₋₄ alkyl) orhalogen-substituted C₁₋₆ alkyl (more preferably, halogen-substitutedC₁₋₄ alkyl) at the 2-, 3-, 5-, and 7-positions is preferred.

A preferred group of compounds according to the present invention arethose wherein the hydrogen atom at the 2-, 3-, 5-, or 7-position of theimidazo 5,1-b!thiazole is attached to the vinyl group present at the3-position of the cephem skeleton and the hydrogen atom at any one ofthe remaining positions is substituted by a methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, sec-butyl, tertbutyl, fluoromethyl,difluoromethyl, 1-fluoroethyl, 1,1-difluoroethyl, 2-fluoroethyl,2,2-difluoroethyl, 2-chloroethyl, or 2,2-dichloroethyl group.

In the formula (I), when R⁷⁺ is present, the compounds represented bythe formula (I) have a positive charge at the 6-position of the imidazo5,1-b!thiazolyl group. As described above, this charge may becountervailed by a charge derived from the absence of R³ to form anintramolecular salt. Alternatively, it may form a salt with anionspecies. Examples of anion species include ions of halogens, such asfluorine, chlorine, bromine, and iodine; ions of inorganic acids, suchas sulfuric acid, nitric acid, phosphoric acid, perchloric acid, andcarbonic acid; ions of carboxylic acids, such as acetic acid,trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lacticacid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelicacid, butyric acid, maleic acid, propionic acid, formic acid, and malicacid; ions of amino acids, such as arginine, aspartic acid, and glutamicacid ion; ions of organic acids, such as methanesulfonic acid andp-toluenesulfonic acid.

The cation species represented by R⁷⁺ is a C₁₋₆ alkyl or C₂₋₆ alkylenegroup with a C₁₋₄ or C₂₋₄ alkylene group being preferred. At least onehydrogen atom on the alkyl and alkylene groups may be substituted.Preferred examples of substituents usable herein include carbamoyl,hydroxyl, amino, and carboxyl groups and halogen atoms, such as fluorineand chlorine.

Preferred are a group of compounds represented by the formula (I)wherein n is 0.

The compounds represented by the formula (I) according to the presentinvention have (E) and (Z) isomers depending upon the position of thesubstituent for the substituted vinyl group at the 3-position, and thepresent invention encompasses the (E) and (Z) isomers or mixturesthereof. Further, isomers attributable to other group(s) in the formula(I) and mixtures thereof are also encompassed in the present invention.

The compounds represented by the formula (I) according to the presentinvention may be present in the form of a salt. Salts usable hereininclude pharmaceutically acceptable nontoxic salts. Preferable examplesof a salt formed at the amino and/or imidazothiazolium group includesalts of hydrohalogenic acids, such as hydrofluoric acid, hydrochloricacid, hydrobromic acid, and hydroiodic acid; salts of inorganic acids,such as sulfuric acid, nitric acid, phosphoric acid, perchloric acid,and carbonic acid; salts of carboxylic acids, such as acetic acid,trichloroacetic acid, trifluoroacetic acid, hydroxyacetic acid, lacticacid, citric acid, tartaric acid, oxalic acid, benzoic acid, mandelicacid, butyric acid, maleic acid, propionic acid, formic acid, and malicacid; salts of amino acids, such as arginine, aspartic acid, andglutamic acid; and salts of organic acids, such as methanesulf onic acidand p-toluenesulfonic acid. Examples of salts formed at the carboxylgroup include alkali metal salts, such as sodium, potassium, and lithiumsalts; alkaline earth metal salts, such as calcium and magnesium salts;ammonium salts; salts of organic amines, such as triethylamine,trimethylamine, diethylamine, pyridine, ethanolamine, triethanolamine,dicyclohexyl amine, procaine, benzyl amine, N-methylpiperidine,N-methylmorpholine, and diethylaniline; salts of basic amino acids, suchas lysine, arginine, and histidine; and salts with organic bases, suchas picoline, dicyclohexylamine, and N,N'-dibenzylethylenediamine salts.

The compounds represented by the formula (I) according to the presentinvention may be provided as metabolically unstable esters which aremetabolized in vivo to give the compounds represented by the formula(I). Such metabolically unstable esters include pivaloyloxymethyl,1-acetoxyethyl, 1-isopropyloxycarbonyloxyethyl, and1-cyclohexyloxycarbonyloxyethyl.

Specific examples of compounds according to the present inventioninclude:

p-methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a mixture of cis andtrans isomers);

sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer) (transisomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a mixtureof cis and trans isomers);

sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer) (transisomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (cis isomer);

(6R,7R)-7- (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(cis isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a mixture of cis andtrans isomers);

sodium (6R,7R)-7- (Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer)(trans isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (a mixture of cis and trans isomers);

(6R,7R)-7- (Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(a mixture of cis and trans isomers);

p-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a mixtureof cis and trans isomers);

sodium (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer)(trans isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (trans isomer);

(6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(trans isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a mixtureof cis and trans isomers);

sodium (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer)(trans isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (trans isomer);

(6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(trans isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomers);

sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (amixture of cis and trans isomers);

sodium (6R,7R)-7- (Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (amixture of cis and trans isomers);

p-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate iodide (a mixture ofcis and trans isomers);

(6R,7R)-7- (Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate (a mixture of cisand trans isomers);

p-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (amixture of cis and trans isomers);

sodium (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomer) (trans isomer);

p-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate iodide (cis isomer);and

(6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate (cis isomer).

Preparation of Compounds

The compounds represented by the general formula (I) according to thepresent invention can be preferably prepared by the following process(A) or (B).

Process (A)

Preferably, the compounds represented by the formula (I) may be preparedby the following scheme: ##STR3## wherein X, R¹, R², R³, R⁴, R⁵, R⁶, andR⁷ are as defined in the formula (I) above, R⁸ represents an aryl group,and W represents a halogen.

Each step will now be described in detail.

Step (i)

A trisubstituted phosphine represented by the formula (III) is reactedwith a compound represented by the formula (II) or a salt thereof.Suitable salts of the compound represented by the formula (II) includesalts with the same bases as exemplified above in connection with thecompounds represented by the formula (I).

Preferably, this reaction is carried out in the presence of a metalhalide, such as an alkali metal halide, such as sodium iodide, potassiumiodide, or sodium bromide. It is carried out in a solvent of acetone,N,N-dimethylformamide, dimethyl sulfoxide, methylene chloride,tetrahydrofuran, ethyl acetate, or a mixture of the above solvents.While the reaction temperature is not particularly limited, in general,it is preferably room temperature. If necessary, the compoundrepresented by the formula (IV) may be isolated.

Step (ii)

A base is allowed to act on the compound represented by the formula (IV)or a salt thereof. Suitable salts of the compound represented by theformula (IV) include salts with the same bases as exemplified above inconnection with the compounds represented by the formula (I).

Preferred examples of bases usable in this step include inorganic bases,for example, alkali metal hydrogencarbonates (for example, sodiumhydrogencarbonate and potassium hydrogencarbonate), alkali carbonates(for example, sodium carbonate and potassium carbonate), alkaline earthmetal carbonates (for example, calcium carbonate), and tri (lower)alkylamines (for example, trimethylamine and triethylamine), pyridine,N-(lower) alkylmorpholine, N-N-di(lower) alkylbenzylamine.

Preferably, the reaction is carried out in a solvent of acetone,tetrahydrofuran, methylene chloride, or water or a mixture of the abovesolvents. While the reaction temperature is not particularly limited, itis preferably room temperature. If necessary, the compound representedby the formula (V) may be isolated.

Step (iii)

An aldehyde represented by the formula (VI) is then reacted with thecompound represented by the formula (V) or a salt thereof. Suitablesalts of the compound represented by the formula (V) include salts withthe same bases as exemplified above in connection with the compoundsrepresented by the formula (I).

Preferably, the reaction is carried out in a solvent of methylenechloride, tetrahydrofuran, dioxane, or a mixture thereof. While thereaction temperature is not particularly limited, in general, thereaction is preferably carried out under cooling or around roomtemperature.

The base and the aldehyde may be simultaneously allowed to act on thecompound represented by the formula (IV) without successively conductingthe steps (ii) and (iii).

Step (iv)

This step is carried out in order to add R⁷ . Therefore, when compoundsrepresented by the formula (I) wherein R⁷ is absent is desired, the step(iv) may be omitted.

An alkyl halide represented by the formula (VII) is reacted with thecompound represented by the formula (VI) or a salt thereof. Suitablesalts of the compound represented by the formula (VI) include salts withthe bases as described above in connection with the formula (I).

Preferably, this reaction is carried out in a solvent of methylenechloride, tetrahydrofuran, dioxane, or a mixture thereof. While thereaction temperature is not particularly limited, in general, thereaction is preferably carried out under cooling or around roomtemperature.

Process (B)

The compounds represented by the formula (I) may be prepared by thefollowing scheme: ##STR4## wherein X, R¹, R², R³, R⁴, R⁵, R⁶, and R⁷ aredefined above in the formula (I) above and W represents a halogen.

In this process, the compounds represented by the formula (I) may beprepared by reacting a compound represented by the formula (VIII), areactive derivative thereof formed at the amino group, or a salt thereofwith a compound represented by the formula (IX), a reactive derivativethereof at the carboxyl group, or a salt thereof. The reaction may becarried out in a solvent, such as water, acetone, dioxane, acetonitrile,chloroform, methylene chloride, tetrahydrofuran, ethyl acetate,N,N-dimethylformamide, or pyridine, or other organic solvents inert tothe reaction. These solvents may be used as a mixture thereof withwater.

Preferred examples of reactive derivatives, formed at the amino group,of the compound represented by the formula (VIII) include Schiff baseimino or enamine isomer, which is a tautomer thereof, prepared byreacting the compound represented by the formula (VIII) with a carbonylcompound, such as an aldehyde or a ketone. Further examples thereofinclude a derivative prepared by reacting the compound of the formula(VIII) with a silyl derivative, such as bis(trimethylsilyl)acetamide, orby reacting the compound of the formula (VIII) with phosphorustrichloride or phosgene.

Suitable salts of the compounds represented by the formulae (VIII) and(IX) include acid addition salts, such as salts with organic acids (forexample, salts with acetic acid, maleic acid, tartaric acid,benzenesulfonic acid, and toluenesulfonic acid) and salts with inorganicacids (for example, salts with hydrochloric acid, hydrobromic acid,sulfuric acid, and phosphoric acid); metal salts, such as alkali metalor alkaline earth metal salts (for example, sodium, potassium, calcium,and magnesium salts); ammonium salts; and organic amines (for example,triethylamine and dicyclohexylamine salts).

Examples of suitable reactive derivatives, formed at the carboxy group,of the compound represented by the formula (IX) include acid halides,acid azides, acid anhydrides, activated amides, and activated esters.More specific examples thereof include: acid chlorides; acid bromides;mixed acid anhydrides with acids, such as substituted phosphoric acids(for example, dialkylphosphoric acids, dibenzylphosphoric acid, andhalogenated phosphoric acids), dialkylphosphorous acids, sulfurous acid,thiosulfuric acid, sulfuric acid, alkyl carbonates (for example, methylcarbonate and ethyl carbonate), aliphatic carbonic acids (for example,pivalic acid, valeric acid, isovaleric acid, and trichloroacetic acid),or aromatic carboxylic acids (for example, benzoic acid); activatedamides with imidazole, dimethylpyrazole, triazole, or tetrazole;activated esters (for example, cyanomethyl ester, methoxymethyl ester,dimethyliminomethyl (CH₃)₂ N═CH--! ester, vinyl ester, propargyl ester,p-nitrophenyl ester, 2,4-dinitrophenyl ester, trichlorophenyl ester,pentachlorophenyl ester, mesylphenyl ester, phenylazophenyl ester,phenyl thioester, p-nitrophenyl thioester, p-cresyl thioester,carboxymethyl thioester, pyranyl ester, pyridyl ester, and 8-quinolylthioester); and N-hydroxy compounds (for example,N,N-dimethylhydroxylamine, 1-hydroxy-2-(1H)-pyridone,N-hydroxysccinimide, N-hydroxyphthalimide, and1-hydroxy-6-chloro-1H-benzotriazole). These reactive derivatives may besuitably selected according to the compound of the formula (IX) as areactant.

In the above reaction, when the compound of the formula (VIII) is usedin a free form or a salt form, condensing agents usable herein include,for example, N,N'-dicyclohexylcarbodiimide,N-cyclohexyl-N'-morpholinocarbodiimide,N-cyclohexyl-N'-(4-diethylaminocyclohexyl)carbodiimide,N-N'-diethylcarbodiimide, N,N'-diisopropylcarbodiimide,N-ethyl-N'-(3-dimethylaminopropyl)carbodiimide,N,N-carbonylbis(2-methylimidazole),pentamethyleneketene-N-cyclohexylimine diphenylketene-N-cyclohexylimine,ethoxyacetylene, 1-alkoxy-1-chloroethylene, trialkyl phosphite, ethylpolyphosphate, isopropyl polyphosphate, phosphorus oxychloride,phosphorus trichloride, thionyl chloride, triphenylphosphine,2-ethyl-5-(m-sulfophenyl)isoxazolium hydroxide intramolecular salt,1-(p-chlorobenzenesulfonyloxy)-6-chloro-1H-benztriazole, and aVilsmeyer's reagent prepared by reacting dimethylformamide with thionylchloride, phosgene, phosphorus oxychloride or the like.

This reaction may also be carried out in the presence of an inorganic ororganic base. Bases usable herein include inorganic bases, such asalkali metal hydrogencarbonates (for example, sodium hydrogencarbonateand potassium hydrogencarbonate), alkaline earth metal carbonates (suchas calcium carbonate), and organic bases, such as tri (lower) alkylamine(for example, trimethylamine and triethylamine), pyridine, N-- (lower)alkylmorpholine, and N,N-di (lower) alkylbenzylamine. The reactiontemperature is not particularly limited. In general, however, thereaction is preferably carried out under cooling or heating.

If necessary, the hydroxy protective group and/or the carboxylprotective group and/or amino protective group may be removed from thecompound (I) of the present invention prepared by the above reaction.Further, if necessary, the carboxyl group may be converted to ametabolically unstable nontoxic ester group. The carboxyl protectivegroup and/or the amino protective group may be removed by any methodwhich is suitably selected according to the protective group to beremoved. For example, the amino protective group may be removed byhydrolysis or reduction, and, in the case of the compound having an acylgroup as the protective group, the protective group may be removed byany conventional method, such as a method wherein the compound isreacted with an imino halogenating agent and then with an iminoetherifying agent, if necessary, followed by hydrolysis. Hydrolysisusing an acid is one of the commonly used methods and may be applied tothe removal of groups, for example, alkoxycarbonyl, formyl, and tritylgroups. Formic acid, trifuloroacetic acid, hydrochloric acid and thelike may be suitably selected according to the type of the amino group.The reaction may be carried out in the absence of a solvent or in thepresence of water, a hydrophilic organic solvent, or a mixture of theabove solvents. When trifluoroacetic acid is used, the reaction may becarried out in the presence of anisole. Any method, such as hydrolysisand reduction, may be applied to the reaction for removing the carboxylprotective group. Further, the hydrolysis, using an acid, which is oneof the commonly used methods may be applied to the removal of groups,for example, silyl and diphenylmethyl groups. The conversion to ametabolically unstable ester may be performed by any common method knownper se, for example, a reaction of the carboxylic acid with a metal saltand a corresponding alkyl halide, such as a pivaloyloxymethyl halide, orthe like in a solvent.

Use of the Compounds/Pharmaceutical Compositions

The compounds according to the present invention have potentantibacterial activity effective against a wide variety of Gram-positiveand Gram-negative bacteria. In particular, they have very potentantibacterial activity against Staphylococcus aureus (MSSA and MRSA) andEnterococcus (faecalis). Therefore, the compounds according to thepresent invention can be used for the treatment of infectious diseasesin animals including humans, caused by various pathogenic fungi.

A pharmaceutical composition comprising as an active ingredient acompound of the present invention or a pharmaceutically acceptable saltthereof can be administered either orally or parenterally (e.g.intravenous injection, intramuscular injection, subcutaneousadministration, rectal administration, or percutaneous administration)to humans or animals other than humans. The pharmaceutical compositioncomprising as an active ingredient a compound of the present inventionmay be made into a preparation suitable for an administration route tobe adopted. Specifically, it may be made into any of the followingpreparations: an injection for intravenous or intramuscular injection; acapsule, a tablet, a granule, a powder, a pill, a subtilized granule ora troche for oral administration; a parenteral preparation; and an oilysuppository. The above-described various preparations can be prepared bya conventional method using an excipient, a filler, a binder, a wettingagent, a disintegrating agent, a surface active agent, a lubricant, adispersing agent, a buffer, a preservative, a solubilizer, anantiseptic, a flavor, a soothing agent, a stabilizer and the like.Examples of the above additives which are nontoxic and employable in thepreparations include milk sugar, fruit sugar, grape sugar, starch,gelatin, magnesium carbonate, synthetic magnesium silicate, talc,magnesium stearate, methyl cellulose, or a salt thereof, gum arabic,polyethylene glycol, syrup, vaseline, glycerol, ethanol, propyleneglycol, citric acid, sodium chloride, sodium sulfite and sodiumphosphate.

The dosage of the compound of the present invention is properlydetermined in consideration of the regimen, the age and sex of apatient, and the conditions of diseases. However, for the treatment ofinfectious diseases, approximately 100 mg to 4000 mg, preferably 500 mgto 2000 mg of the compound is generally administered per day per adultindividual at one time or several times.

EXAMPLES

The present invention will now be described with reference to thefollowing examples.

Preparation 1 Imidazo 5,1-b!thiazole-3-carbaldehyde

In 20 ml of dichloromethane was suspended 0.211 g of3-hydroxymethylimidazo 5,1-b!thiazole. Manganese dioxide (1.1 g) wasadded to the suspension, and the mixture was stirred at room temperaturefor 16 hr. The reaction mixture was filtered, and the filtrate wasevaporated to dryness under reduced pressure to give 0.146 g (yield 71%)of the title compound.

NMR (CDCl₃): δ 7.11 (1H, s), 7.42 (1H, s), 8.16 (1H, s), 8.66 (1H, s)

Preparation 2 3-Methylimidazo 5,1-b!thiazole-2-carbaldehyde

The procedure of Preparation 1 was repeated, except that 0.554 g of2-hydroxymethyl-3-methylimidazo 5,1-b!thiazole was used as the startingcompound. Thus, 0.468 g (yield 83%) of the title compound was obtained.

NMR (CDCl₃): δ 2.78 (3H, s), 7.13 (1H, s), 7.43 (1H, s), 8.15 (1H, s),8.69 (1H, s)

Example 1 p-Methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (1:3 mixture of cis andtrans isomers)

Sodium iodide (50 mg) was added at room temperature to a solution of 240mg of p-methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylateand 87 mg of triphenylphosphine in 5 ml of acetone, and the mixture wasstirred for 1.5 hr. The reaction mixture was evaporated to dryness underreduced pressure, and 10 ml of methylene 2chloride was added thereto.Imidazo 5,1-b!thiazole-3-carbaldehyde (138 mg) was added, and 15 ml of a5% aqueous sodium hydrogencarbonate solution was added thereto. Themixture was stirred at room temperature for 4 hr and then separated, andthe aqueous layer was extracted with methylene chloride. The extract wascombined with the organic layer, and the combined extract and organiclayer were washed with a saturated saline solution, dried over anhydrousmagnesium sulfate, and concentrated under reduced pressure. Theconcentrate was purified by Sephadex LH 20 column chromatography(eluent: chloroform:methanol=1:1) to give 218 mg (yield 81%) of thetitle compound.

NMR (CDCl₃): δ 3.04 (1/4H, d, J=18 Hz), 3.43 (1/4H, d, J=18 Hz), 3.54(3/4H, d, J=18 Hz), 3.63 (3/4H, d, J=18 Hz), 3.79 (3/4H, s), 3.81 (9/4H,s), 4.07 (3H, s), 5.22 (1/2H, s), 5.25 (3/2H, s), 7.22 (1H, s), 7.25(1/4H, s), 7.33 (3/4H, s), 8.53 (3/4H, s), 8.80(1/4H, s)

Example 2 Sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer) (transisomer)

Trifluoroacetic acid (2.5 ml) was added dropwise to a solution of 218 mgof p-methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a 1:3 mixture of cisand trans isomers) in 1 ml of anisole under ice cooling. The mixture wasstirred under ice cooling for one hr, and cold isopropyl ether was addedthereto. The resultant precipitate was collected by filtration, washedwith isopropyl ether, dried, and neutralized with a 5% aqueous sodiumhydrogencarbonate solution. Thereafter, separation and purification wereperformed by column chromatography on Diaion HP 20 and Sephadex LH 20 insequence to give the title compound cis isomer 23.1 mg (yield 18%) andtrans isomer 58.3 mg (yield 45%)!.

NMR (D₂ O)(cis form) δ 3.35 (1H, d, J=18 Hz), 3.59 (1H, d, J=18 Hz),3.96 (3H, s), 5.26 (1H, d, J=4 Hz), 5.78 (1H, d, J=4 Hz), 6.48 (1H, d,J=12 Hz), 6.72 (1H, d, J=12 Hz), 6.98 (1H, s), 7.23 (1H, s), 7.41 (1H,s), 8.79 (1H, s), (trans form) δ 3.68 (1H, d, J=18 Hz), 3.79 (1H, d,J=18 Hz), 3.98 (3H, s), 5.30 (1H, d, J=4 Hz), 5.82 (1H, d, J=4 Hz), 6.66(1H, d, J=17 Hz), 7.00 (1H, s), 7.21 (1H, s), 7.22 (1H, s), 7.30 (1H, d,J=17 Hz), 8.55 (1H, s)

Example 3 p-Methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (1:3 mixtureof cis and trans isomers)

The procedure of Example 1 was repeated, except that 308 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-chloromethyl-3-cephem-4-carboxylatewas used as the starting compound. Thus, 272 mg (yield 80%) of the titlecompound was obtained.

NMR (CDCl₃) δ 3.06 (1/4H, d, J=18 Hz), 3.42 (1/4H, d, J=18 Hz), 3.53(3/4H, d, J=18 Hz), 3.66 (3/4H, d, J=18 Hz), 3.82 (3H, s), 5.24 (2H, s),7.22 (1H, s), 7.25 (1/4H, s), 7.35 (3/4H, s), 8.55 (3/4H, s), 8.82(1/4H, s)

Example 4 Sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer) (transisomer)

Trifluoroacetic acid (2.5 ml) was added dropwise to a solution of 272 mgof p-methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a 1:3mixture of cis and trans isomers) and 500 mg of p-methoxyphenol in 0.5ml of anisole under ice cooling. The mixture was stirred under icecooling for one hr, and cold isopropyl ether was added thereto. Theresultant precipitate was collected by filtration, washed with isopropylether, dried, and neutralized with a 5% aqueous sodium hydrogencarbonatesolution. Thereafter, the reaction mixture was purified by columnchromatography on Diaion HP 20 and Sephadex LH 20 in sequence to givethe title compound cis isomer 11.2 mg (yield 10%) and trans isomer 30.2mg (yield 24%)!.

NMR (D₂ O) (cis form) δ 3.33 (1H, d, J=17 Hz), 3.55 (1H, d, J=17 Hz),5.27 (1H, d, J=5 Hz), 5.83 (1H, d, J=5 Hz), 6.49 (1H, d, J=11 Hz), 6.72(1H, d, J=11 Hz), 6.96 (1H, s), 7.04 (1H, s), 7.16 (1H, s), 8.80 (1H,s), (trans form) δ 3.75 (1H, d, J=18 Hz), 3.85 (1H, d, J=18 Hz), 5.35(1H, d, J=5 Hz), 5.90 (1H, d, J=5 Hz), 6.76 (1H, d, J=17 Hz), 7.02 (1H,s), 7.16 (1H, s), 7.19 (1H, s), 7.37 (1H, d, J=17 Hz), 8.55 (1H, s)

Example 5 p-Methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (cis isomer)

p-Methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl-3-cephem-4-carboxylate (cis isomer)(98.4 mg) was dissolved in 3 mg of methylene chloride. Methyl iodide(1.5 ml) was added to the solution, and the mixture was allowed to reactat room temperature for 16 hr. The reaction mixture was evaporated todryness under reduced pressure. The concentrate was purified by SephadexLH 20 column chromatography (eluent: chloroform: methanol=1:1) to give81.2 mg (yield 73%) of the title compound.

NMR (CDCl₃) δ 3.07 (1H, d, J=18 Hz), 3.42 (1H, d, J=18 Hz), 4.10 (3H,s), 4.24 (3H, s), 5.22 (2H, s), 7.32 (1H, s), 7.35 (1H, s), 9.55 (3/4H,s)

Example 6 (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(cis isomer)

The procedure of Example 4 was repeated, except that 81.2 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-(2-tritylaminothiazol-4-yl)-2-trityloxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (cis isomer) was used as the starting compound. Thus, 18.1 mg(yield 51%) of the title compound was obtained.

NMR (D₂ O) δ 3.36 (1H, d, J=17 Hz), 3.62 (1H, d, J=17 Hz), 4.08 (3H, s),5.29 (1H, d, J=5 Hz), 5.82 (1H, d, J=5 Hz), 6.46 (1H, d, J=11 Hz), 6.75(1H, d, J=11 Hz), 6.79 (1H, s), 7.36 (1H, s), 7.62 (1H, s), 9.20 (1H, s)

Example 7 p-Methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (1:3 mixture of cis andtrans isomers)

The procedure of Example 1 was repeated, except that 243 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylatewas used as the starting compound. Thus, 216 mg (yield 76%) of the titlecompound was obtained.

NMR (CDCl₃) δ 1.33 (3/4H, t, J=7 Hz), 1.36 (1/4H, t, 7 Hz), 3.07 (1/4H,d, J=18 Hz), 3.40 (1/4H, d, J=18 Hz), 3.54 (3/4H, d, J=18 Hz), 3.67(3/4H, d, J=18 Hz), 4.07 (3H, s), 4.26 (2H, q, J=7 Hz), 5.24 (1/2H, s),5.27 (3/2H, s), 7.24 (1H, s), 7.23 (1/4H, s), 7.37 (3/4H, s), 8.58(3/4H, s), 8.81 (1/4H, s)

Example 8 Sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer) (transisomer)

The procedure of Example 2 was repeated, except that 216 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a 1:3 mixture of cisand trans isomers) was used as the starting compound. Thus, the titlecompound cis isomer: 20.0 mg (yield 15%), trans isomer: 62.6 mg (yield48%)! was obtained.

NMR (D₂ O) (cis form) δ 1.31 (3H, t, J=6 Hz), 3.36 (1H, d, J=18 Hz),3.60 (1H, d, J=18 Hz), 4.27 (2H, q, J=6 Hz), 5.29 (1H, d, J=5 Hz), 5.81(1H, d, J=5 Hz), 6.52 (1H, d, J=12 Hz), 6.76 (1H, d, J=12 Hz), 7.00 (1H,s), 7.22 (1H, s), 7.38 (1H, s), 8.81 (1H, s), (trans form) δ 1.35 (3H,t, J=6 Hz), 3.74 (1H, d, J=18 Hz), 3.85 (1H, d, J=18 Hz), 4.29 (2H, q,J=6 Hz), 5.34 (1H, d, J=5 Hz), 5.86 (1H, d, J=5 Hz), 6.73 (1H, d, J=15Hz), 7.02 (1H, s), 7.27 (2H, s), 7.36 (1H, d, J=15 Hz), 8.63 (1H, s)

Example 9 p-Methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (1:3 mixture of cis and trans isomers)

The procedure of Example 5 was repeated, except that 250 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl-3-cephem-4-carboxylate (a 1:3 mixture of cisand trans isomers) was used as the starting compound. Thus, 255 mg(yield 88%) of the title compound was obtained.

NMR (CDCl₃) δ 1.33 (3/4H, t, J=7 Hz), 1.36 (1/4H, t, J=7 Hz), 3.07(1/4H, d, J=18 Hz), 3.39 (1/4H, d, J=18 Hz), 3.57 (3/4H, d, J=18 Hz),3.67 (3/4H, d, J=18 Hz), 4.07 (3H, s), 4.11 (3H, s), 4.28 (2H, q, J=7Hz), 5.22 (1/2H, s), 5.25 (3/2H, s), 7.24 (1H, s), 7.34 (1/4H, s), 7.44(3/4H, s), 9.27 (3/4H, s), 9.46 (1/4H, s)

Example 10 (6R,7R)-7-(Z)-2-(2-Aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(1:3 mixture of cis and trans isomers)

The procedure of Example 2 was repeated, except that 255 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (a 1:3 mixture of cis and trans isomers) was used as the startingcompound. Thus, 101 mg (yield 66%) of the title compound was obtained.

NMR (D₂ O) δ 1.29 (9/4H, t, J=7 Hz), 1.32 (3/4H, t, J=7 Hz), 3.36 (3/4H,d, J=18 Hz), 3.62 (3/4H, d, J=18 Hz), 3.76 (1/4H, d, J=18 Hz), 3.85(1/4H, d, J=18 Hz), 4.08 (9/4H, s), 4.12 (3/4H, s), 4.27 (1/2H, q, J=7Hz), 4.30 (3/2H, q, J=7 Hz), 5.28 (3/4H, d, J=4 Hz), 5.32 (1/4H, d, J=4Hz), 5.78 (3/4H, d, J=4 Hz), 5.84 (1/4H, d, J=4 Hz), 6.45 (1/4H, d, J=12Hz), 6.74 (1/4H, d, J=12 Hz), 6.77 (3/4H, d, J=16 Hz), 6.79 (3/4H, s),6.98 (1/4H, s), 7.35 (3/4H, d, J=16 Hz), 7.36 (1/4H, s), 7.52 (3/4H, s),7.62 (1/4H, s), 7.65 (3/4H, s), 9.20 (1/4H, s), 9.34 (3/4H, s)

Example 11 p-Methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (transisomer)

The procedure of Example 1 was repeated, except that 480 mg ofp-methoxybenzyl(6R,7R)-7-r(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylatewas used as the starting compound. Thus, 298 mg (yield 55%) of the titlecompound was obtained.

NMR (CDCl₃) δ 3.77 (1H, d, J=18 Hz), 3.89 (1H, d, J=18 Hz), 4.11 (3H,s), 5.25 (2H, s), 5.88 (1H, d, J=5 Hz), 6.70 (1H, d, J=15 Hz), 7.09 (2H,s), 7.33 (1H, d, J=15 Hz), 8.36 (1H, s)

Example 12 Sodium (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (transisomer)

The procedure of Example 2 was repeated, except that 198 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (transisomer) was used as the starting compound. Thus, 41.5 mg (yield 35%) ofthe title compound was obtained.

NMR (D₂ O) δ 3.75 (1H, d, J=18 Hz), 3.86 (1H, d, J=18 Hz), 5.31 (1H, d,J=5 Hz), 5.85 (2H, d, J=56 Hz), 5.88 (1H, d, J=5 Hz), 6.67 (1H, d, J=15Hz), 7.08 (1H, s), 7.11 (1H, s), 7.31 (1H, d, J=15 Hz), 8.34 (1H, s)

Example 13 p-Methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (trans isomer)

The procedure of Example 5 was repeated, except that 100 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (transisomer) was used as the starting compound. Thus, 94.6 mg (yield 83%) ofthe title compound was obtained.

NMR (CDCl₃) δ 3.76 (1H, d, J=18 Hz), 3.89 (1H, d, J=18 Hz), 4.10 (6H,s), 5.25 (2H, s), 6.70 (1H, d, J=15 Hz), 7.38 (1H, d, J=15 Hz), 7.55(1H, s), 9.29 (1H, s)

Example 14 (6R,7R)-7-(Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(trans isomer)

The procedure of Example 2 was repeated, except that 94.6 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (trans isomer) was used as the starting compound. Thus, 27.5 mg(yield 56%) of the title compound was obtained.

NMR (D₂ O) δ 3.74 (1H, d, J=18 Hz), 3.84 (1H, d, J=18 Hz), 4.12 (3H, s),5.33 (1H, d, J=5 Hz), 5.86 (2H, d, J=54 Hz), 5.87 (1H, d, J=5 Hz), 6.76(1H, d, J=15 Hz), 7.35 (1H, d, J=15 Hz), 7.52 (1H, s), 7.65 (1H, s),9.31 (1H, s)

Example 15 p-Methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (1:3 mixtureof cis and trans isomers)

The procedure of Example 1 was repeated, except that 497 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylatewas used as the starting compound. Thus, 505 mg (yield 91%) of the titlecompound was obtained.

NMR (CDCl₃) δ 1.55-2.10 (8H, m), 3.09 (1/4H, d, J=18 Hz), 3.39 (1/4H, d,J=18 Hz), 3.58 (3/4H, d, J=18 Hz), 3.66 (3/4H, d, J=18 Hz), 4.08 (3H,s), 5.23 (2H, s), 7.04 (1H, s), 7.10 (1/4H, s), 7.17 (3/4H, s), 7.44(3/4H, s), 7.46 (1/4H, s)

Example 16 Sodium (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer)(trans isomer)

The procedure of Example 2 was repeated, except that 243 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (a mixtureof cis and trans isomers) was used as the starting compound. Thus, thetitle compound cis isomer: 23.5 mg (yield 16%), trans isomer: 69.1 mg(yield 46%)! was obtained.

NMR (D₂ O) (cis form) δ 1.55-2.10 (8H, m), 3.40 (1H, d, J=18 Hz), 3.63(1H, d, J=18 Hz), 5.26 (1H, d, J=5 Hz), 5.86 (1H, d, J=5 Hz), 6.48 (1H,d, J=11 Hz), 6.69 (1H, d, J=11 Hz), 7.06 (1H, s), 7.16 (1H, s), 7.36(1H, s) (trans form) δ 1.55-2.10 (8H, m), 3.69 (1H, d, J=18 Hz), 3.82(1H, d, J=18 Hz), 5.32 (1H, d, J=5 Hz), 5.84 (1H, d, J=5 Hz), 6.69 (1H,d, J=15 Hz), 7.10 (1H, s), 7.14 (1H, s), 7.35 (1H, d, J=15 Hz)

Example 17 p-Methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (trans isomer)

The procedure of Example 5 was repeated, except that 94.6 mg ofp-methoxybenzyl (6R,7R)-7- (Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3- 2-(imidazo5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (trans isomer) was usedas the starting compound. Thus, 93.4 mg (yield 86%) of the titlecompound was obtained.

NMR (CDCl₃) δ 1.55-2.10 (8H, m), 3.58 (1H, d, J=18 Hz), 3.66 (1H, d,J=18 Hz), 4.08 (3H, s), 4.12 (3H, s), 5.23 (2H, s), 6.82 (1H, d, J=15Hz), 7.10 (1H, d, J=15 Hz), 7.44 (1H, s), 7.66 (1H, s), 8.33 (1H, s)

Example 18 (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-cyclopentyloxyiminoacetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylate(trans isomer)

The procedure of Example 2 was repeated, except that 94.6 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-cyclopentyloxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(6-methylimidazo 5,1-b!thiazolium-3-yl)vinyl!-3-cephem-4-carboxylateiodide (trans isomer) was used as the starting compound. Thus, 42.2 mg(yield 81%) of the title compound was obtained.

NMR (D₂ O) δ 1.55-2.10 (8H, m), 3.70 (1H, d, J=18 Hz), 3.81 (1H, d, J=18Hz), 4.10 (3H, s), 5.35 (1H, d, J=5 Hz), 5.85 (1H, d, J=5 Hz), 6.81 (1H,d, J=15 Hz), 7.12 (1H, d, J=15 Hz), 7.55 (1H, s), 7.68 (1H, s), 8.35(1H, s)

Example 19 p-Methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomers)

Sodium iodide (50 mg) was added at room temperature to a solution of 240mg of p-methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylateand 87 mg of triphenylphosphine in 5 ml of acetone, and the mixture wasstirred for 1.5 hr. The reaction mixture was evaporated to dryness underreduced pressure, and 10 ml of methylene chloride was added thereto.

3-Methylimidazo 5,1-b!thiazole-2-carbaldehyde (150 mg) was added, and 15ml of a 5% aqueous sodium hydrogencarbonate solution was added thereto.The reaction mixture was stirred at room temperature for 4 hr and thenseparated, and the aqueous layer was extracted with methylene chloride.The extract was combined with the organic layer, and the combinedextract and organic layer were washed with a saturated saline solution,dried over anhydrous magnesium sulfate, and concentrated under reducedpressure. The concentrate was purified by Sephadex LH 20 columnchromatography (eluent: chloroform:methanol=1:1) to give 225 mg (yield82%) of the title compound.

NMR (CDCl₃) δ 2.33 (3H, s), 3.06 (1H, d, J=18 Hz), 3.45 (1H, d, J=18Hz), 3.95 (1H, s), 4.07 (3H, s), 5.22 (2H, s), 6.36 (1H, d, J=12 Hz),6.55 (1H, d, J=12 Hz), 7.00 (2H, s), 8.08 (1H, s)

Example 20 Sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomer)

The procedure of Example 2 was repeated, except that 225 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomer) was used as the starting compound. Thus, 60.7 mg (yield 45%) ofthe title compound was obtained.

NMR (D₂ O) δ 2.38 (3H, s), 3.42 (1H, d, J=18 Hz), 3.66 (1H, d, J=18 Hz),3.98 (3H, s), 5.38 (1H, d, J=5 Hz), 5.84 (1H, d, J=5 Hz), 6.34 (1H, d,J=12 Hz), 6.56 (1H, d, J=12 Hz), 6.99 (1H, s), 7.02 (1H, s), 8.09 (1H,s)

Example 21 p-Methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (2:1mixture of cis and trans isomers)

The procedure of Example 19 was repeated, except that 500 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylatewas used as the starting compound. Thus, 416 mg (yield 73%) of the titlecompound was obtained.

NMR (CDCl₃) δ 1.33 (1H, t, J=7Hz), 1.36 (2H, t, 7 Hz), 2.38 (3H, s),3.08 (2/3H, d, J=18 Hz), 3.42 (2/3H, d, J=18 Hz), 3.54 (1/3H, d, J=18Hz), 3.67 (1/3H, d, J=18 Hz), 4.08 (3H, s), 4.26 (2/3H, q, J=7 Hz), 4.30(4/3H, q, J=7 Hz), 5.24 (2H, s), 7.00 (1H, s), 7.23 (2/3H, s), 7.35(1/3H, s), 8.33 (1/3H, s), 8.41 (2/3H, s)

Example 22 Sodium (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (2:1mixture of cis and trans isomers)

The procedure of Example 2 was repeated, except that 208 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (a2:1 mixture of cis and trans isomers) was used as the starting compound.Thus, 63.0 mg (yield 50%) of the title compound was obtained.

NMR (D₂ O) δ 1.29 (1H, t, J=7 Hz), 1.31 (2H, t, J=7 Hz), 2.39 (1H, s),2.42 (2H, s), 3.42 (2/3H, d, J=18 Hz), 3.67 (2/3H, d, J=18 Hz), 3.77(1/3H, d, J=18 Hz), 3.88 (1/3H, d, J=18 Hz), 4.26 (3H, q, J=7Hz), 5.25(1/3H, d, J=5 Hz), 5.39 (2/3H, d, J=5 Hz), 5.85 (1H, d, J=5 Hz), 6.40(2/3H, d, J=11 Hz), 6.58 (2/3H, d, J=11 Hz), 6.82 (1/3H, d, J=15 Hz),7.00 (1H, s), 7.05 (2/3H, d, J=15 Hz), 7.08 (1/3H, s), 7.16 (2/3H, s),8.30 (1/3H, s), 8.35 (2/3H, s)

Example 23 p-Methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate iodide (2:1 mixtureof cis and trans isomers)

The procedure of Example 5 was repeated, except that 208 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3-methylimidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (a2:1 mixture of cis and trans isomers) was used as the starting compound.Thus, 188 mg (yield 78%) of the title compound was obtained.

NMR (CDCl₃) δ 1.33 (3H, t, J=7Hz), 2.38 (3H, s), 3.10 (2/3H, d, J=18Hz), 3.42 (2/3H, d, J=18 Hz), 3.55 (1/3H, d, J=18 Hz), 3.69 (1/3H, d,J=18 Hz), 4.08 (3H, s), 4.12 (3H, s), 4.26 (2H, q, J=7 Hz), 5.26 (2H,s), 7.00 (1H, s), 7.53 (2/3H, s), 7.55 (1/3H, s), 9.30 (1/3H, s), 9.38(2/3H, s)

Example 24 (6R,7R)-7-(Z)-2-(2-aminothiazol-4-yl)-2-ethoxyiminoacetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate (2:1 mixture of cisand trans isomers)

The procedure of Example 2 was repeated, except that 188 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-ethoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate iodide (a 1:2mixture of cis and trans isomers) was used as the starting compound.Thus, 42.1 mg (yield 42%) of the title compound was obtained.

NMR (D₂ O) δ 1.31 (3H, t, J=7 Hz), 2.51 (1H, s), 2.47 (2H, s), 3.44(2/3H, d, J=18 Hz), 3.69 (2/3H, d, J=18 Hz), 3.76 (1/3H, d, J=18 Hz),3.84 (1/3H, d, J=18 Hz), 3.86 (2/3H, d, J=18 Hz), 4.06 (3H, s), 4.27(2H, q, J=7 Hz), 5.30 (1/3H, d, J=5 Hz), 5.40 (2/3H, d, J=5 Hz), 5.85(1H, d, J=5 Hz), 6.49 (2/3H., d, J=11 Hz), 6.61 (2/3H, d, J=11 Hz), 6.86(1/3H, d, J=15 Hz), 6.98 (1H, s), 7.01 (1/3H, s), 7.47 (2/3H, d, J=15Hz), 7.52 (1/3H, s), 9.11 (1/3H, s), 9.15 (2/3H, s)

Example 25 p-Methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(3-imidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (2:1mixture of cis and trans isomers)

The procedure of Example 19 was repeated, except that 240 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-chloromethyl-3-cephem-4-carboxylatewas used as the starting compound. Thus, 229 mg (yield 84%) of the titlecompound was obtained.

NMR (CDCl₃) 2.38 (3H, s), 3.11 (2/3H, d, J=18 Hz), 3.42 (2/3H, d, J=18Hz), 3.52 (1/3H, d, J=18 Hz), 3.68 (1/3H, d, J=18 Hz), 4.12 (3H, s),5.24 (2H, s), 5.83 (2H, d, J=55 Hz), 7.00 (1H, s), 7.08 (2/3H, s), 8.05(1/3H, s), 8.30 (2/3H, s)

Example 26 Sodium (6R,7R)-7-(Z)-2-(5-amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(imidazo 5,1-b!thiazol-3-yl)vinyl!-3-cephem-4-carboxylate (cis isomer)(trans isomer)

The procedure of Example 2 was repeated, except that 114 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(3-imidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (a 2:1mixture of cis and trans isomers) was used as the starting compound.Thus, the title compound cis isomer: 16.5 mg (yield 24%), trans isomer:13.5 mg (yield 19%)! was obtained.

NMR (D₂ O) (cis form) δ 2.39 (3H, s), 3.41 (1H, d, J=18 Hz), 3.66 (1H,d, J=18 Hz), 5.38 (1H, d, J=5 Hz), 5.83 (1H, d, J=55 Hz), 5.89 (1H, d,J=5 Hz), 6.37 (1H, d, J=11 Hz), 6.57 (1H, d, J=11 Hz), 7.07 (1H, s),8.26 (1H, s) (trans form) δ 2.38 (3H, s), 3.73 (1H, d, J=18 Hz), 3.85(1H, d, J=18 Hz), 5.35 (1H, d, J=5 Hz), 5.84 (1H, d, J=55 Hz), 5.90 (1H,d, J=5 Hz), 6.30 (1H, d, J=15 Hz), 6.82 (1H, d, J=15 Hz), 6.94 (1H, s),8.02 (1H, s)

Example 27 p-Methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate iodide (cis isomer)

The procedure of Example 5 was repeated, except that 114 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazol-3-yl)acetamido!-3-2-(3-imidazo 5,1-b!thiazol-2-yl)vinyl!-3-cephem-4-carboxylate (cisisomer) was used as the starting compound. Thus, 103 mg (yield 78%) ofthe title compound was obtained.

NMR (CDCl₃) 2.37 (3H, s), 3.11 (1H, d, J=18 Hz), 3.40 (1H, d, J=18 Hz),4.09 (3H, s), 4.12 (3H, s), 5.23 (2H, s), 5.88 (2H, d, J=55 Hz), 7.44(1H, s), 9.08 (1H, s)

Example 28 (6R,7R)-7-(Z)-2-(5-Amino-1,2,4-thiadiazol-3-yl)-2-fluoromethoxyiminoacetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate (cis isomer)

The procedure of Example 2 was repeated, except that 103 mg ofp-methoxybenzyl (6R,7R)-7-(Z)-2-fluoromethoxyimino-2-(5-tritylamino-1,2,4-thiadiazole-3-yl)acetamido!-3-2-(3,6-dimethylimidazo5,1-b!thiazolium-2-yl)vinyl!-3-cephem-4-carboxylate iodide (cis isomer)was used as the starting compound. Thus, 30.2 mg (yield 41%) of thetitle compound was obtained.

NMR (D₂ O) δ 2.45 (3H, s), 3.43 (1H, d, J=18 Hz), 3.67 (1H, d, J=18 Hz),4.06 (3H, s), 5.40 (1H, d, J=5 Hz), 5.85 (1H, d, J=55 Hz), 5.93 (1H, d,J=5 Hz), 6.40 (1H, d, J=11 Hz), 6.58 (1H, d, J=11 Hz), 7.50 (1H, s),9.16 (1H, s)

Preparation Examples

Preparation for Injection

A pharmaceutical composition containing a compound according to thepresent invention is aseptically charged into vials so that each vialcontains 1000 mg (potency) of the compound of the invention.

Capsule Preparation

Compound of the invention 250 parts (potency)

Milk sugar 60 parts (potency)

Magnesium stearate 5 parts (potency)

The above ingredients are homogeneously mixed, and the mixture ischarged into capsules so that each capsule contains 250 mg (potency) ofthe compound of the invention.

Soft Capsule Preparation for Rectal Administration

Olive oil 160 parts

Polyoxyethylene lauryl ether 10 parts

Sodium hexametaphosphate 5 parts

25 parts (potency) of the compound of the present invention is added toand homogeneously mixed with a base comprising the above ingredients,and the mixture is charged into soft capsules for rectal administrationso that each capsule may contain 250 mg (potency) of the compound of theinvention.

Antibacterial Activity

The antibacterial activity of the compounds according to the presentinvention was assayed by the conventional two-fold dilution method. Theminimum inhibitory concentrations (MIC) were as follows. The measurementwas carried out in the following manner: 10⁶ CFU/ml of a bacterium to betested was inoculated on a Medium N for disc susceptibility test(manufactured by Nissui Pharmaceutical Co., Ltd.), and cultivated at 35°C. for 18 to 20 hr.

                  TABLE 1    ______________________________________               Trans   Trans               isomer  isomer    Test strain               of Ex. 4                       of Ex. 14  Cefdinir                                        Cefpirome    ______________________________________    St. aureus 0.20    0.20       0.20  0.39    209PJC-1    St. aureus 3.13    3.13       6.25  12.5    M133    St. aureus 12.5    6.25       >100  50    M126    Ent. hirae 1.56    12.5       50    3.13    ATCC8043    Ent. faecalis               0.78    3.13       25    25    W-73    E. coli 255               0.78    0.10       50    0.20    E. coli GN206               0.20    <0.025     25    <0.02    5M. morganii               1.56    0.78       25    0.20    1510    E. cloacae 0.39    0.05       6.25  0.05    G-0008    Ser.       0.39    0.05       25    0.05    marcescens    No. 1    ______________________________________

What is claimed is:
 1. A cephem derivative represented by the formula(I): ##STR5## wherein X represents CH or N, R¹ represents hydrogen or anamino protective group selected from the group consisting ofalkoxycarbonyl, acyl and trityl,R² represents hydrogen; C₁₋₄ alkyl inwhich one or more hydrogen atoms may be substituted by halogen orcarboxyl, C₁₋₄ alkoxycarbonyl, carbamoyl, N-C₁₋₄ alkylcarbamoyl, cyano,amino, or C₁₋₄ alkylamino; C₂₋₄ alkenyl; C₂₋₄ alkynyl; or C₃₋₆cycloalkyl, R³ is absent or represents hydrogen, a salt forming cation,or a carboxyl protective group selected from the group consisting ofaryl, lower alkyl, lower alkoxymethyl, lower alkylthiomethyl, loweralkanoyloxymethyl, lower alkoxycarbonyloxyalkyl, loweralkylcarbonyloxyalkyl, and optionally substituted(2-oxo-1,3-dioxolen-4-yl)methyl, R⁴, R⁵, and R⁶, which may be the sameor different, each representhydrogen; C₁₋₄ alkoxy; C₁₋₄ alkylthio;cyano; carboxyl; C₁₋₄ alkoxycarbonyl; carbamoyl; N-C₁₋₄ alkylcarbamoyl;formyl; amino in which one or more hydrogen atoms may be substituted byformyl, C₁₋₄ alkylcarbonyl, or C₁₋₄ alkylsulfonyl; halogen; C₁₋₄ alkylin which one or more hydrogen atoms may be substituted by a groupselected from the group consisting of hydroxyl, C₁₋₄ alkoxy, mercapto,C₁₋₄ alkylthio and cyano, halogen, carboxyl, C₁₋₄ alkoxycarbonyl,carbamoyl, N-C₁₋₄ alkylcarbamoyl, formyl, alkylcarbonyl, hydroxyimino,C₁₋₄ alkoxyimino, amino, formylamino, C₁₋₄ alkylcarbonylamino,halogen-substituted C₁₋₄ alkylcarbonylamino, carbamoyloxy, N-C₁₋₄alkylcarbamoyloxy, C₁₋₄ alkylsulfonylamino, ureido, N--C₁₋₄ alkylureido,C₁₋₄ alkylcarbonylamino and imino C₁₋₄ alkylamino; C₃₋₆ cycloalkyl; C₂₋₄alkenyl; or C₂₋₄ alkynyl or any two of R⁴, R⁵, and R⁶ may togetherrepresent C₃₋₆ alkylene where one or more methylene groups in thisalkylene group may be replaced by --NH--, --O--, --S--, or --CO--, R⁷⁺is absent or represents a cation of C₁₋₆ alkyl, substituted C₁₋₆ alkyl,or substituted C₁₋₆ alkylene, and n is an integer of 0 to 1; or apharmaceutically acceptable salt or ester thereof.
 2. The compoundaccording to claim 1, wherein R² represents hydrogen, C₁₋₄ alkyl inwhich one or more hydrogen atoms may be substituted by halogen or, C₃₋₆cycloalkyl.
 3. The compound according to claim 1, wherein R³ representsa metabolically unstable carboxyl protective group.
 4. The compoundaccording to claim 1, wherein R³ represents a cation of an alkali metalor an alkaline earth metal.
 5. The compound according to claim 1, whichis in the form of an intramolecular salt with R³ being absent.
 6. Thecompound according to claim 1, wherein R⁴, R⁵, or R⁶ is C₁₋₄ alkyloptionally substituted by halogen.
 7. The compound according to claim 6,wherein C₁₋₄ alkyl is present in the 2-, 3-, 5-, or 7-position of theimidazo 5,1-b!thiazolyl moiety.
 8. The compound according to claim 1,wherein the imidazo 5,1-b!thiazolyl moiety is attached in its 3- or2-position to the cephem skeleton.
 9. A pharmaceutical compositioncomprising a compound according to any one of claims 2 to 8 or 1together with a pharmaceutically acceptable carrier.
 10. A method fortreating an infectious disease caused by Staphylococcus aureus orEnterococcus faecalis, comprising administering an effective amount of acompound according to any one of claims 2 to 8 or 1 to a mammal.
 11. Themethod according to claim 10, wherein the mammal is a human being.